ClinVar Miner

Submissions for variant NM_000445.5(PLEC):c.13192G>A (p.Ala4398Thr) (rs200361523)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000725165 SCV000334590 uncertain significance not provided 2015-09-01 criteria provided, single submitter clinical testing
GeneDx RCV000725165 SCV000566838 uncertain significance not provided 2017-03-14 criteria provided, single submitter clinical testing The A4398T variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The A4398T variant is observed in 33/64330 (0.05%) alleles from individuals of European background (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved in mammals; however, missense variants in nearby residues have not been reported in the Human Gene Mutation Database in association with PLEC-related disorders (Stenson et al., 2014). In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.
Invitae RCV000540878 SCV000650185 uncertain significance Epidermolysa bullosa simplex and limb girdle muscular dystrophy; Epidermolysis bullosa simplex, Ogna type; Epidermolysis bullosa simplex with pyloric atresia; Limb-girdle muscular dystrophy, type 2Q; Epidermolysis bullosa simplex with nail dystrophy 2018-12-10 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 4398 of the PLEC protein (p.Ala4398Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs200361523, ExAC 0.05%) but has not been reported in the literature in individuals with a PLEC-related disease. ClinVar contains an entry for this variant (Variation ID: 196853). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change with uncertain impact on protein function. Because it is found in the population at an appreciable frequency, this variant is not anticipated to cause disease. However, the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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